tbuckley/cabot-search huggingface dataset:
A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183).
Authors: Maha H. A. Hussain, Masha Kocherginsky, Parminder Singh, Zin Myint, Di Maria Jiang, Elizabeth Marie Wulff-Burchfield, Elad Sharon, Richard Piekarz, Joshua J Meeks, David James VanderWeele
Journal: Journal of Clinical Oncology (2023)

506 Background: Despite response to systemic therapy, few metastatic urothelial carcinoma (mUC) patients (pts) achieve durable responses. Mutations in the COMPASS-related proteins KMT2D, KMT2C, and KDM6A are found in 66% of UC patients suggesting histone regulation may be an acquired mechanism of tumor viability. We previously found regression of UC in mice when treated with EZH2 inhibitor, tazemetostat. In vivo administration of tazemtostat enhanced the immune response with direct regulation of cytokines and antigen recognition machinery (MHCI and MHCII). We hypothesized that restoration of epigenetic imbalance, combined with immunotherapy, may improve outcomes in mUC pts. Methods: ETCTN 10183 (NCT03854474) is a pilot study evaluating the efficacy of tazemetostat 800 mg BID + pembrolizumab 200 mg every 3 weeks for cisplatin-refractory (Cohort A) or cisplatin/chemo-ineligible advanced UC (Cohort B) pts, with N=12 pts in each cohort. The primary objective is to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives include RECIST-based response rate, safety, and progression-free survival. The maximum planned treatment duration is 2 years. Translational objectives include defining total and COMPASS-related genes tumor mutational burden, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: In the safety lead-in phase, 6 mUC pts were treated. There were no dose-limiting toxicities (DLTs). The RP2D for tazemetostat was established at 800 mg BID. Here we report results of fully accrued cohort A (N=12); 67% males, 33% females, 83% white, 8.3% Black, and 25% Hispanic/Latino ethnicity. The primary sites of UC were: bladder (n=9, 75%), renal pelvis (n=2, 17%), and ureter (n=1, 8.3%). The median (interquartile range, IQR) time since primary diagnosis was 1.1 years (0.7, 1.9); 11/12 patients had non-nodal metastatic disease; 10/12 had 1 or more visceral/bone metastasis. Median number of treatment cycles was 5 (IQR: 3-11; range 1-35). Median duration on protocol treatment was 12 weeks (IQR: 7-30; range 3-107 weeks). Three pts had treatment related grade 3/4 AEs: grade 4 sepsis (n=1), grade 3 lymphopenia (n=2); anemia, increased alkaline-phosphatase, and HSV oral infection (n=1 each). Best response was partial response (PR) in 3 pts (25%) and 3 (25%) had stable disease. Median PFS was 3.1 months (95%CI: 2.3-NA), and median overall survival was 8.0 months (95% CI: 4.7 – NA). Conclusions: The RP2D dose for tazemetostat is 800 mg + 200 mg Pembrolizumab q 3 weeks. The combination was feasible, well tolerated, and resulted in durable responses in poor-risk chemo-refractory UC patients. Clinical trial information: 03854474 .
Comparative cost-effectiveness of alternative imaging and surveillance schedules for testicular seminoma in the TRISST trial.
Authors: Dacheng Huo, Robert A Huddart, Fay Helen Cafferty, Laura Murphy, Gordon J. S. Rustin, Syed A Sohaib, Francesca Schiavone, Richard S. Kaplan, Johnathan K Joffe, Mark Sculpher, Saramago Pedro
Journal: Journal of Clinical Oncology (2023)

408 Background: Risk of radiation exposure from standard computed tomography (CT) surveillance is a major concern in the management of stage I seminoma testis patients. The TRISST randomized trial (NCT00589537) demonstrated that effective monitoring could be achieved with a reduced scan schedule or using Magnetic Resonance Imaging (MRI) instead of CT. Here, TRISST data is used to evaluate the economic consequences and health outcomes of different surveillance schedules in seminoma patients in the UK. Methods: 669 men were randomized to 4 surveillance groups undergoing 7 CTs over 5 years, 3 CTs over 3 years, 7 MRIs, or 3 MRIs of the retroperitoneum. Resource use (including investigations, scans, hospitalisations and treatment for relapse) and health outcomes data (EQ-5D 3L) on each patient were collected at baseline and over a period of 6 years after randomization. Health resources were costed using publicly available national unit costs. Within-trial mean total costs and quality-adjusted life years (QALYs) were estimated for each alternative schedule. Under the perspective of the UK health system, cost-effectiveness was evaluated using a cost per QALY gained framework. Probabilistic sensitivity analysis was used to reflect parameter uncertainty and evaluate results robustness. Results: Since only 82 men (12%) relapsed, most health resource consumption (76%) happened during the disease-free period. Patients undergoing 7 MRIs yielded, on average, slightly higher health benefits (5.20 QALYs) but at higher costs (GBP £6,632, see table). Compared to 7 CTs, 7 MRIs was estimated to have 63% probability of being cost-effective at a system willingness to pay threshold of £20k/QALY. 3 MRIs had similar costs and benefit to 7 CTs, whereas 3CTs was more expensive than 7 CTs and 3 MRIs, providing marginal additional benefits. Conclusions: Overall, small differences exist in total costs and total QALYs between different strategies. A 7 scan MRI schedule yielded more health benefits than other strategies, but at higher costs. Considering possible capacity constraints with MRI, the reduced radiation exposure relative to CT, and non-inferiority for clinical outcomes in the primary analysis, a 3 scan MRI schedule may be the best option to replace current CT-based longer surveillance practice. Clinical trial information: NCT00589537 . [Table: see text]
The usefulness of meflin expression in cancer-associated fibroblasts as a predictive marker for immune checkpoint inhibitor in clear cell renal cell carcinoma.
Authors: Takayuki Owaki, Yuki Miyai, Yushi Naito, Tomoyasu Sano, Atsushi Enomoto
Journal: Journal of Clinical Oncology (2023)

699 Background: Tumor is composed of various cells, including not only cancer cells, but also immune cells, vascular endothelial cells and cancer associated fibroblasts (CAFs). CAFs generally work to promote cancer malignancy by secreting growth factors, promoting angiogenesis and producing extra cellular matrix. However, depletion of these CAFs accelerated tumor progression. Therefore, it is a common belief that there are two kinds of CAFs, cancer-promoting CAFs and cancer-restraining CAFs. Recently, our research group identified cancer-restraining CAFs expressing Meflin as a marker in pancreatic cancer. Furthermore, our research group reported that Meflin can be a good predictive marker for ICI in non-small cell lung cancer. This time, we performed a similar analysis for clear cell renal cell carcinoma (ccRCC), to confirm whether Meflin is universally a good predictive marker for ICI or not. Methods: This analysis was performed as a retrospective observational study and conducted in accordance with the Helsinki Declaration for Human Research and approved by the Ethics Committee of Nagoya University Graduate School of Medicine (approval number: 2020-0321).We identified 21 eligible patients with ccRCC who received ICI from 2017 to Mar 2019. We collected FFPE tissue and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA in-situ hybridization (ISH). Then, we assessed the number of Meflin-positive CAFs and divided the patients into Meflin-high (15% and more CAFs express Meflin) and -Low groups, followed by the evaluation of the clinical outcomes, objective response rate (ORR) and overall survival (OS). Results: Patients were followed-up until the Aug 2022. 13 patients were divided into Meflin-high and 8 patients were divided into Meflin-low groups. Analysis revealed that 9 (69.23%) of 13 Meflin-high patients responded to ICI. In contrast, none (0%) of 8 Meflin-low patients showed any significant response (p-value: 0.0046). Furthermore, Kaplan–Meier survival analysis revealed, the Meflin-high group had a significantly favorable prognosis in OS (p-value:0.0137, hazard ratio 0.2959[0.06933 to 0.7097]). Conclusions: This analysis concluded that Meflin is a good predictive biomarker for ICI in ccRCC.
SunRISe-4: TAR-200 plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or refuse neoadjuvant platinum-based chemotherapy.
Authors: Sarah P. Psutka, Christopher Cutie, Sumeet Kaur Bhanvadia, Kirk A. Keegan, Wendy Crist, Shaozhou Ken Tian, John Maffeo, Bradley Raybold, Marietta Kashmer, Mohamad Hasan, Xiang Li, Neil Beeharry, Shibu Thomas, Hui Tian, Thomas Powles
Journal: Journal of Clinical Oncology (2023)

TPS584 Background: Standard of care for patients (pts) with MIBC is radical cystectomy (RC) with neoadjuvant systemic platinum-based chemotherapy (PBC); however, systemic chemotherapy is associated with significant toxicity. TAR-200 is an intravesical drug delivery system that provides local continuous gemcitabine release within the bladder. SunRISe-4 (NCT04919512) is an open-label, multicenter, randomized phase 2 study designed to assess the efficacy and safety of neoadjuvant TAR-200 + systemic cetrelimab (CET [anti–programmed death-1 antibody]) vs neoadjuvant CET alone in pts with MIBC scheduled for RC who are ineligible for or refuse neoadjuvant PBC. Methods: Eligibility criteria: age ≥18 years, Eastern Cooperative Oncology Group performance status of 0 or 1, histologically confirmed cT2-T4a MIBC with absence of nodal or metastatic disease at screening, and residual intravesical tumor volume of ≤3 cm prior to randomization. Pts will be stratified by completeness of transurethral resection of bladder tumor (TURBT; visibly complete vs incomplete and ≤3 cm) and tumor stage (cT2 vs cT3-4a) at initial diagnosis. Pts (N≈160) will be randomized 5:3 to receive TAR-200 + CET (Cohort 1, n≈100) or CET alone (Cohort 2, n≈60). In Cohort 1, TAR-200 (225 mg gemcitabine) will be placed intravesically at the initial treatment visit; TAR-200 will be removed and replaced over a 12-week period. In both cohorts, CET will be serially dosed intravenously over the same timeframe. Primary disease assessments include axial imaging (at screening and Week 6), centralized review of TURBT (initial diagnostic TURBT or debulking TURBT for pts with lesions &gt;3 cm after initial TURBT) as well as RC and nodal tissue specimens. After RC, all pts will have follow-up visits from Weeks 4 to 108 post RC (end of study). The primary outcome measure is the pathologic complete response rate at time of RC. Secondary outcome measures include safety, tolerability, and recurrence-free survival (per Response Evaluation Criteria in Solid Tumors 1.1 or histologic evidence). Exploratory outcome measures include patient-reported cancer-related quality of life (Functional Assessment of Cancer Therapy–Bladder questionnaire) and pathologic overall response rate at RC. Overall survival and time to symptomatic progression, pharmacokinetics, biomarker analysis, and immunogenicity will also be evaluated. As of September 12, 2022, 2 of 160 planned pts have been enrolled and randomized, and recruitment is ongoing at ≈95 sites. Clinical trial information: NCT04919512 .
Histopathological upstage, recurrence, and survival in a population-based cohort of surgically treated patients with clinical T1b renal cell carcinoma.
Authors: Sven Lundstam, Andreas Karlsson Rosenblad, Borje Ljungberg
Journal: Journal of Clinical Oncology (2023)

731 Background: T1 renal cell carcinoma (RCC) is considered to have a low malignant potential. Partial nephrectomy (PN) is recommended for nephron sparing whenever technically feasible also for T1b RCC. Despite a favorable prognosis there remains a risk for upstaging and recurrence, and the place for PN in clinical T1b tumors is questionable. Therefore, we have characterized these variables and overall survival (OS) in a real-world population-based cohort of patients with clinical T1b RCC. Methods: Patients without metastases registered in the National Swedish Kidney Cancer Register (99% of RCCs diagnosed in Sweden) 2005-2014 with clinical T1b (&gt; 4-7 cm), surgically treated and with a follow-up of ≥ 5 years were included. Results: There were 2137 patients (1300 males, 837 females) with a mean age of 66 years; 82% had clear cell (ccRCC), 11% papillary (pRCC) and 6% chromophobe (chRCC) RCC. Radical nephrectomy (RN) was performed in 1836 patients and PN in 301 patients. After histopathological examination 435 (20%) were upstaged to pathological (p) T3: 21% of ccRCCs, 13% of pRCC and 20% of chRCCs. Recurrent disease after ≥ 5-years follow-up was diagnosed in 127 (29%) pT3 patients and in 238 (14%) with pT1b, 322 (18%) in ccRCC, 127 (11%) in pRCC and 6(5%) in chRCC. Lung metastases occurred in 52% of patients with recurrencies and 144 (39%) of these had two or more metastatic sites. Patients with pT3RCC had a 67% five-year OS compared to 83% in pT1b patients (Log-rank test, p&lt;0.001). Regardless of other factors, patients treated with PN had a higher 5-year OS of 86% compared to 79% in patients treated with RN (Log-rank test, p=0.006). In multivariable analyses, lower age, female sex, smaller tumors, N0, pRCC and chRCC, and pT1b stage were significantly associated with longer survival. A hazard ratio of 0.93 [95% CI 0.65-1.32] for PN indicated that PN was non-inferior to the treatment with RN in patients with clinical T1bRCC. Conclusions: Clinical T1bRCC is a malignant disease with risk for upstaging and tumor recurrence. Nonetheless, the results indicate that PN is non-inferior to the treatment with RN in clinical T1bRCC and support the recommendation to offer PN also in these patients.
Cabozantinib + nivolumab in adult patients with advanced or metastatic renal cell carcinoma: A retrospective, non-interventional study in a real-world cohort.
Authors: Thomas Hilser, Christopher Darr, Guenter Niegisch, Marco Julius Schnabel, Susan Foller, Lorine Haeuser, Stefanie Zschaebitz, Jonas Lewerich, Merle Anders-Meyn, Philipp Ivanyi, Katrin Schlack, Viktor Grünwald
Journal: Journal of Clinical Oncology (2023)

628 Background: Standard treatment for 1st-line mRCC are IO-combinations. Data from real-world collectives are rare. In this multicenter study, we therefore evaluated safety and effectiveness of cabozantinib/nivolumab in Germany. Methods: Data were collected retrospectively from eight GU cancer centres in Germany. Patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) were eligible. Treatment with cabozantinib 40 mg orally + nivolumab 240 or 480 mg i.v. was mandatory and administered according to routine care. Adverse events (AEs) were reported according to CTCAE 5.0. Objective response rate per RECIST 1.1 and Progression Free Survival (PFS) were calculated from start of treatment to progression or death. Descriptive statistics and KM-plots were utilized, where appropriate. Results: 67 suitable pts (62.7% male) with median age of 67.6 years were included. The most common histology was clear cell RCC (ccRCC) in 67.2% (n=45). Nephrectomy was performed in 56.7% (n=38). ECOG 0-1 was 76.1% (n=51). IMDC scores were: 0 in 11 (16.4%), ≥ 1 in 45 (67.1%), missing in 11 pts (16.4%). 29.9% (n=20) required dose reductions or interruptions. Partial response was documented in 46.3% (n=31), stable disease in 32.8% (n=22), and progressive disease in 4.5% (n=3) as best overall response. Data were missing in 14.9% (n=10). Median Follow-up was 8.3 mo, median treatment duration was 6.0 months, PFS rate at 6 month was 81.9% overall (79.3% for ccRCC; 85.9% for non-ccRCC). AEs (all grades) were reported in 82.1% (n=55) and 47.8% (n=32) for grade 3-5. Elevated liver enzymes (40.3%), diarrhea (22.4%) and hand-foot-syndrome (20.9%) were the 3 most frequent AEs of any grade and causality. Conclusions: In this real-world cohort of mRCC pts. cabozantinib + nivolumab was shown to be safe and feasible. While no new safety signals were reported, a reduced dose was frequently utilized. Our data support the use of cabozantinib + nivolumab as a first-line standard. Major limitations were the retrospective data capture and short follow-up of our study.
Differential treatment response of prostate and metastatic lesions in patients with newly diagnosed metastatic prostate cancer.
Authors: Baris Esen, Hulya Seymen, Okan Falay, Kayhan Tarim, Mert Kılıç, Sevil Bavbek, Yakup Kordan, Derya Tilki, Tarik Esen, Mehmet Onur Demirkol
Journal: Journal of Clinical Oncology (2023)

56 Background: We aimed to evaluate the response of primary tumor to systemic treatment in patients with newly diagnosed mPCa with serial PSMA PET/CT scans. Methods: A total of 43 patients with newly diagnosed mPCa who had significant prostatic PSMA uptake at baseline PSMA PET/CT (bPSMA) and underwent at least one follow-up PSMA PET/CT (fPSMA) after receiving systemic treatment were included in the study. Those who received any definitive treatment at localized stage and those who underwent radiotherapy to prostate before fPSMA were excluded. Prostatic and metastatic PSMA response after systemic treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) as recommended by guidelines. Discordant behavior between prostate and metastases was defined as the condition when metastatic lesions are responding (CR or PR) to systemic treatment while prostate had progressed or vice versa. CHAARTED criteria was applied to categorize patients according to the volume of metastatic disease. Results: The mean age of patients at bPSMA was 67.7 ± 8.5 years. The median PSA at bPSMA was 31.7 ng/dL (IQR: 11.3 – 106.0). Patient characteristics and treatments are summarized. The median time interval between bPSMA and the first fPSMA was 5.7 months (IQR: 4.6 – 7.5). Nine patients (20.9%) had CR, 25 (58.1%) had PR, 5 (11.6%) had SD and 4 (9.3%) had PD at prostate following systemic treatment. Patients with low-volume disease had prostatic CR twice more commonly than those with high-volume disease (27.3% vs 14.3%). In 6 (13%) cases, a significant PSMA uptake at prostate was detected despite a complete response of all metastatic sites. Discordant treatment responses at the prostate and metastatic sites were observed in 6 out of 43 (16%) patients. Conclusions: Discordant behavior between prostate and metastases are not rare in mPCa. Almost one-fourth of patients with low-volume mPCa achieved a complete prostatic response with systemic treatment only. Prostatic response on PSMA PET/CT following systemic treatment can be used to select ideal patients for the treatment of the primary tumor in patients with mPCa. [Table: see text]
Baseline circulating soluble factors as predictors of immune-related adverse events (irAEs) in patients (pts) with metastatic clear cell renal carcinoma (mRCC) treated with nivolumab: A translational NIVOREN GETUG-AFU 26 study.
Authors: Lucia Carril-Ajuria, Marie Naigeon, Cécile Dalban, Aude Desnoyer, Nathalie Rioux-Leclercq, Catherine Sautès-Fridman, Maxime Meylan, Yann-Alexandre Vano, Benoit Beusenlick, Salem Chouaib, Caroline de Oliveira, Florence Tantot, Ronan Flippot, Bernard Escudier, Laurence Albiges, Nathalie Chaput
Journal: Journal of Clinical Oncology (2023)

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (&lt;3, p=0.003) at baseline and a good LIPI score (p=0.014) were also associated with a higher risk of all grade AEs. No other significant associations were found between circulating soluble factors and all grade irAEs. No significant associations were found between circulating solubles factors/systemic inflammatory markers and the presence of severe irAEs Conclusions: Using the cut-off values previously identified, we observed that lower baseline levels of circulating IL-6 were associated with an increased risk of all grade irAEs. Good LIPI patients and those with a lower dNLR also presented a higher risk of all grade irAEs. Baseline circulating soluble factors and systemic inflammatory markers failed to demonstrate a significant association with the development of severe irAEs.
Characterization of anti-cancer immune response associated with immune-related adverse events in patients with kidney cancer.
Authors: Taigo Kato, Kazuma Kiyotani, Yu Ishizuya, Yoshiyuki Yamamoto, Koji Hatano, Atsunari Kawashima, Norio Nonomura
Journal: Journal of Clinical Oncology (2023)

711 Background: Some reports showed promising clinical efficacy among patients who discontinued immune checkpoint inhibitors (ICIs) due to immune-related adverse events (irAEs). In this study, we aimed to characterize T cell receptor (TCR) repertoire repertoire in peripheral blood mononuclear cells (PBMCs) before and after ICI treatment, and at the onset of irAE for understanding of irAE-provoked anti-cancer immune responses. Methods: We collected metastatic tumor tissues and peripheral blood samples from 54 patients with advanced kidney cancer before anti-programmed cell death protein 1 (PD-1) treatment and 1 month after treatment initiation. Furthermore, we applied a next-generation sequencing approach to characterize TCR repertoires using tumor tissues and PBMCs. Results: The number of irAEs was significantly higher in responder for nivolumab (p &lt; 0.0001). We also confirmed that irAE present patients had better progression-free survival and overall survival when compared to irAE absent patients (p=0.0010 and p=0.011, respectively). TCR repertoire analysis revealed that diversity index for TCR alpha and beta in irAE present patients were significantly decreased at 1 month after nivolumab, indicating expansion of certain T cell clones even in PBMCs after nivolumab. We also examined morishita index to measure T cell similarity between pre- and post nivolumab samples. As a result, irAE present patients had significantly lower similarity than irAE absent patients, indicating a larger change in the T cell clones, and inducing newly expanded T cell clones in post-nivolumab PBMC samples. Importantly, irAE present patients had significantly higher numbers of peripheral T cell clones shared with metastatic tumor-infiltrating T cells than those in irAE absent patients at 1 month after nivolumab (as per the 100 most abundant T cell clonotypes in the peripheral blood; p=0.038). Conclusions: Our findings revealed that a certain number of irAE-provoked T cell clones can also circulate systemically and attack tumor cells in distant regions, leading to durable response in the patients with irAEs.